Alcohol abuse exacerbates human immunodeficiency virus type 1 (HIV-1) infection by decreasing compliance with anti-retroviral therapy and increasing opportunistic infections such as pneumocystis (PCP). Host defense against PCP and other pathogens requires robust innate immune responses by alveolar macrophages as well as an intact alveolar epithelial barrier to limit lung injury, both of which are impaired by alcohol abuse. Importantly, not all manifestations of HIV-1 infection can be attributed to viral infection itself, and there is evidence that HIV-1-related proteins including gp120 and Tat can induce oxidative stress and directly damage target tissues. Investigators in this proposal have identified that chronic ethanol ingestion also causes severe and previously unrecognized oxidative stress within the alveolar space, leading to alveolar epithelial and alveolar macrophage dysfunction. In parallel (or perhaps as a consequence) ethanol ingestion impairs granulocyte/macrophage colony-stimulating factor (GM-CSF) receptor expression and signaling in alveolar epithelial cells and macrophages, and recombinant GM-CSF restores alveolar epithelial cell and macrophage function in ethanol-fed rats. Remarkably, these abnormalities in oxidative stress and GM-CSF signaling are also present in HIV-1 transgenic rats and are exacerbated by chronic ethanol ingestion. New preliminary studies that form the foundation for this exploratory R21 proposal suggest that HIV-1-related proteins and chronic ethanol ingestion may act via different mechanisms to profoundly impair GM-CSF signaling within the alveolar space, which has enormous implications for pulmonary host defense in HIV-1-infected individuals, particularly in the context of alcohol abuse. This project will study the interactions between chronic ethanol ingestion and HIV-1-related protein expression on GM-CSF signaling and GM-CSF- dependent functions within the alveolar epithelium and macrophage, and how this affects clearance of PCP from the lung in vivo, in a relevant animal model. In parallel, novel adjunctive therapies including procysteine (an antioxidant) and recombinant GM-CSF will be tested to determine if alveolar epithelial and macrophage function can be improved even in the face of chronic HIV-1-related protein expression +/- ethanol ingestion. Ultimately, the long-term goal of this project is to identify effective new adjunctive therapies that can complement standard treatment and enhance lung function in HIV-1-infected individuals. [unreadable] [unreadable] [unreadable]